Glucokinase (GK) also referred as hexokinase IV or hexokinase D belongs to the family of hexokinases. It catalyzes phosphorylation of hexoses such as D-glucose, D-mannose, D-fructose and 2-deoxy-D-glucose by MgATP2−. (Cardenas, M. L. et. al., Biochim. Biophys. Acta, 1401, 242-264 (1998)). Glucokinase differs from other hexokinases in terms of its enzyme kinetics. It has positive co-operativity and low affinity for glucose. In contrast to other hexokinases, it does not get inhibited by its end product, glucose-6-phosphate.
Glucokinase is principally expressed in liver and pancreatic β-cells. The glucose concentration at which glucokinase exhibits half maximum activity is 8 mM. The other three hexokinases get saturated at very low glucose concentration (<1 mM). Therefore, the flux of glucose through GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (˜10 mM) levels following carbohydrate containing meal [Printz, R. G., Magnuson, M. A. and Granner, D. K. in Ann. Rev. Nutrition, vol. 13, (R. E. Olson, D. M. Bier, and D. B. McCormik, eds.) Annual Review Inc. Palo Alto, Calif., pages 463-496, 1993]. A decade ago, these and subsequent findings led to the hypothesis that GK functions as glucose sensor in hepatocyte and pancreatic β-cells. (Meglasson, M. D. et. al. Amer. J. Physiol., 246, E1-E13, 1984).
Recently, transgenic animal study has confirmed that GK does play a critical role in whole-body glucose-homeostasis. Animals those do not express GK die within few days of birth with severe diabetes while animals with GK overexpression have improved glucose tolerance [Grupe, A. et. al. Cell, 83, 69-78, (1995); Ferrie, T. et. al. FASEB J., 10, 1213-1218, (1996)].
There are both, activating and deactivating mutations reported for GK gene. Deactivating mutations cause diabetes called type 2 maturity onset diabetes of young (MODY2) (Vionnet, N., et. al., Nature, 356, 721-22, (1992); Matschinsky, F. M., et. al. J. Clin. Invest. 92, 2092-98, (1993)) while activating mutations cause persistent hyperinsulinemia hypoglycemia of infancy (PHHI) (Christesen, H. B. et. al., Diabetes, 51, 1240-46, (2002)). These literature data supports the notion that small molecules as glucokinase activators will help to treat diabetes particularly type II diabetes.
International (PCT) Patent Publication No. WO 01/44216 discloses 2,3-disubstituted trans olefin N-heteroaromatic or urido proprionamides as glucokinase activators which increase insulin secretion in the treatment of type II diabetes. U.S. Pat. No. 0,225,286 discloses hydantoin compounds which are active as glucokinase activators and useful to increase insulin secretion for treating type II diabetes. European Patent Publication No. EP 1305301 discloses alpha-acyl & alpha-heteroatom-substituted benzene acetamide as glucokinase activators. International (PCT) Patent Publication No. WO2005/080359 discloses benzamide derivatives and their use as glucokinase activating agents. International (PCT) Patent Publication No. WO2005/080360 discloses benzamide derivatives as glucokinase activators. International (PCT) Patent Publication No. WO2005/121110 discloses heteroaryl benzamide derivatives for use as glucokinase activators in the treatment of diabetes. International (PCT) Patent Publication No. WO 2006/040528 discloses phenoxy benzamide compounds with utility in the treatment of type II diabetes and obesity. International (PCT) Patent Publication No. WO 2007/007042 describes heteroaryl benzamide derivatives for use as glucokinase activators in the treatment of diabetes.
However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime
We herein disclose novel compounds of general Formula (I) which are glucokinase activators and are useful for the prevention and treatment of diseases states mediated by Glucokinase (GK).